Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Mental health disorders are more common in patients with Hodgkin lymphoma and may negatively impact overall survival.

BACKGROUND: Long-term mental health outcomes were characterized in patients who were diagnosed with Hodgkin lymphoma (HL), and risk factors for the development of mental health disorders were identified. METHODS: Patients who were diagnosed with HL between 1997 and 2014 were identified in the Utah Cancer Registry. Each patient was matched with up to five individuals from a general population cohort identified within the Utah Population Database, a unique source of linked records that includes patient and demographic data. RESULTS: In total, 795 patients who had HL were matched with 3575 individuals from the general population. Compared with the general population, patients who had HL had a higher risk of any mental health diagnosis (hazard ratio, 1.77; 95% confidence interval, 1.57-2.00). Patients with HL had higher risks of anxiety, depression, substance-related disorders, and suicide and intentional self-inflicted injuries compared with the general population. The main risk factor associated with an increased risk of being diagnosed with mental health disorders was undergoing hematopoietic stem cell transplantation, with a hazard ratio of 2.06 (95% confidence interval, 1.53-2.76). The diagnosis of any mental health disorder among patients with HL was associated with a detrimental impact on overall survival; the 10-year overall survival rate was 70% in patients who had a mental health diagnosis compared with 86% in those patients without a mental health diagnosis (p < .0001). CONCLUSIONS: Patients who had HL had an increased risk of various mental health disorders compared with a matched general population. The current data illustrate the importance of attention to mental health in HL survivorship, particularly for patients who undergo therapy with hematopoietic stem cell transplantation.

Tumor-associated antigen-specific T cells with nivolumab are safe and persist in vivo in relapsed/refractory Hodgkin lymphoma.

Hodgkin lymphoma (HL) Reed Sternberg cells express tumor-associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA-specific T cells (TAA-Ts) targeting WT1, PRAME, and Survivin were safe and associated with prolonged time to progression in solid tumors. Hence, we evaluated whether TAA-Ts when given alone or with nivolumab were safe and could elicit antitumor effects in vivo in patients with relapsed/refractory (r/r) HL. Ten patients were infused with TAA-Ts (8 autologous and 2 allogeneic) for active HL (n = 8) or as adjuvant therapy after hematopoietic stem cell transplant (n = 2). Six patients received nivolumab priming before TAA-Ts and continued until disease progression or unacceptable toxicity. All 10 products recognized 1 or more TAAs and were polyfunctional. Patients were monitored for safety for 6 weeks after the TAA-Ts and for response until disease progression. The infusions were safe with no clear dose-limiting toxicities. Patients receiving TAA-Ts as adjuvant therapy remain in continued remission at 3+ years. Of the 8 patients with active disease, 1 patient had a complete response and 7 had stable disease at 3 months, 3 of whom remain with stable disease at 1 year. Antigen spreading and long-term persistence of TAA-Ts in vivo were observed in responding patients. Nivolumab priming impacted TAA-T recognition and persistence. In conclusion, treatment of patients with r/r HL with TAA-Ts alone or in combination with nivolumab was safe and produced promising results. This trial was registered at www.clinicaltrials.gov as #NCT022039303 and #NCT03843294.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

AIM: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. METHODS: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. RESULTS: We discovered positive associations between FROH and CLL (ß = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (ß = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (ß = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. CONCLUSION: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk.

AIM: Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity. METHODS: We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity. RESULTS: We identified a genome-wide significant region (P = 1.9 × 10-7, LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression. CONCLUSION: SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).

Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration.

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

NCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

Phase I trial of isatuximab monotherapy in the treatment of refractory multiple myeloma.

This phase I dose-escalation/expansion study evaluated isatuximab (anti-CD38 monoclonal antibody) monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Patients progressing on or after standard therapy received intravenous isatuximab (weekly [QW] or every 2 weeks [Q2W]). The primary objective was to determine the maximum tolerated dose (MTD) of isatuximab. Overall, 84 patients received ≥ 1 dose of isatuximab. The MTD was not reached; no cumulative adverse reactions were noted. The most frequent adverse events were infusion reactions (IRs), occurring in 37/73 patients (51%) following introduction of mandatory prophylaxis. IRs were mostly grade 1/2, occurred predominantly during Cycle 1, and led to treatment discontinuation in two patients. CD38 receptor occupancy reached a plateau of 80% with isatuximab 20 mg/kg (highest dose tested) and was associated with clinical response. In patients receiving isatuximab ≥ 10 mg/kg, overall response rate (ORR) was 23.8% (15/63), including one complete response. In high-risk patients treated with isatuximab 10 mg/kg (QW or Q2W), ORR was 16.7% (3/18). Median (range) duration of response at doses ≥ 10 mg/kg was 25 (8-30) weeks among high-risk patients versus 36 (6-85) weeks for other patients. In conclusion, isatuximab demonstrated a manageable safety profile and clinical activity in patients with RRMM.

Elevated IgM and abnormal free light chain ratio are increased in relatives from high-risk chronic lymphocytic leukemia pedigrees.

Abnormal serum immunoglobulin (Ig) free light chains (FLC) are established biomarkers of early disease in multiple B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Heavy chains have also been shown to be biomarkers in plasma cell disorders. An unanswered question is whether these Ig biomarkers are heritable, i.e., influenced by germline factors. CLL is heritable but highly heterogeneous. Heritable biomarkers could elucidate steps of disease pathogenesis that are affected by germline factors, and may help partition heterogeneity and identify genetic pleiotropies across malignancies. Relatives in CLL pedigrees present an opportunity to identify heritable biomarkers. We compared FLCs and heavy chains between relatives in 23 high-risk CLL pedigrees and population controls. Elevated IgM (eIgM) and abnormal FLC (aFLC) ratio was significantly increased in relatives, suggesting that these Ig biomarkers are heritable and could offer risk stratification in pedigree relatives. Within high-risk CLL pedigrees, B-cell lymphoid malignancies were five times more prevalent in close relatives of individuals with eIgM, prostate cancer was three times more prevalent in relatives of individuals with aFLC, and monoclonal B-cell lymphocytosis increased surrounding individuals with normal Ig levels. These different clustering patterns suggest Ig biomarkers have the potential to partition genetic heterogeneity in CLL and provide insight into distinct heritable pleiotropies associated with CLL.

Drug-free macromolecular therapeutics induce apoptosis in cells isolated from patients with B cell malignancies with enhanced apoptosis induction by pretreatment with gemcitabine.

Drug-free macromolecular therapeutics (DFMT) is a new paradigm for the treatment of B cell malignancies. Apoptosis is initiated by the biorecognition of complementary oligonucleotide motifs at the cell surface resulting in crosslinking of CD20 receptors. DMFT is composed from two nanoconjugates: 1) bispecific engager, Fab'-MORF1 (anti-CD20 Fab' fragment conjugated with morpholino oligonucleotide), and 2) a crosslinking (effector) component P-(MORF2)X (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer grafted with multiple copies of complementary morpholino oligonucleotide). We evaluated this concept in 44 samples isolated from patients diagnosed with various subtypes of B cell malignancies. Apoptosis was observed in 65.9% of the samples tested. Pretreatment of cells with gemcitabine (GEM) or polymer-gemcitabine conjugate (2P-GEM) enhanced CD20 expression levels thus increasing apoptosis induced by DFMT. These positive results demonstrated that DFMT has remarkable therapeutic potential in various subtypes of B cell malignancies.

Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era.

PURPOSE: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed. RESULTS: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

Efficacy of salvage chemotherapy in diffuse large B cell lymphoma with primary treatment failure according to putative cell of origin.

We evaluated outcome of 235 primary treatment failure (PTF) diffuse large B-cell lymphoma (DLBCL) patients based on salvage chemotherapy regimen and putative cell-of-origin (COO). Patients were divided into two groups; group A (n = 38) received high-dose cytarabine containing regimen, either DHAP or ESHAP. Patients in group B (n = 197) received ifosfamide, carboplatin, and etoposide (ICE) +/- rituximab. No difference in overall response rates (CR + PR) was observed based on salvage chemotherapy regimen and COO. After adjustment for the presence of ultra high-risk features, overall survival of germinal center B-cell like (GCB) DLBCL patients in group A was not significantly different from survival in group B (HR 0.86, 95% CI 0.46-1.60, p = .64). Similarly, within non-GCB DLBCL cohort, survival in group A was comparable to group B (HR 0.53, 95% CI 0.20-1.44, p = .21). We did not find an outcome difference between two commonly used salvage chemotherapy regimens in patients with PTF DLBCL based on COO.

Genetically Determined Height and Risk of Non-hodgkin Lymphoma.

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.

Transgenerational effects of chemotherapy: Both male and female children born to women exposed to chemotherapy have fewer children.

BACKGROUND: There is little known about the transgenerational effect of chemotherapy. For example, chemotherapy is known to decrease fecundity in women. But if women are able to have offspring after chemotherapy exposure, do these children also have decreased fecundity? METHODS: This study is a retrospective cohort study utilizing the Utah Population Database (UPDB), a comprehensive resource that links birth, medical, death and cancer records for individuals in the state of Utah. The male and female children (F1 generation) of chemotherapy-exposed women (F0 generation) were identified. The number of live births (F2 generation) to this F1 generation was compared to two sets of chemotherapy-unexposed, matched controls using conditional Poisson regression models (regression coefficient, 95% confidence interval, P-value). The first unexposed was established using the general population and the second unexposed was established using first cousins to the F1 generation. RESULTS: The exposed F1 individuals had 77.2% fewer children (-1.48; -2.51 to -0.70; p = 0.001) relative to the unexposed general population. F1 males had 86.9% fewer children (-2.03; -4.91 to -0.51; p = 0.005) and F1 females had 70.5% fewer children (-1.22; -2.40 to -0.36; p = 0.016). When comparing to their unexposed cousins, the F1 generation (both sexes combined) had 74.3% (-1.36; -2.82 to -0.29; p = 0.029) fewer children. CONCLUSION: The sons and daughters (F1 generation) of chemotherapy-exposed women have fewer live births when compared to both matched, unexposed general population and cousin controls. Chemotherapy may have a transgenerational effect in exposed women which needs further investigation.

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia.

Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women). Three, 5, and 4 patients had good-, intermediate-, and poor-risk disease, respectively. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had morphologic complete remission after 1 induction (CR1). Eight patients were alive at a median follow-up of 24 months (4 patients in CR1). Three patients received an allogeneic stem cell transplant in CR1. Median disease-free survival was 14.8 months. Median overall survival was not attained at the maximum follow-up time of 29.4 months. No CX-01-associated serious adverse events occurred. Median day to an untransfused platelet count of at least 20 × 109/L was 21. CX-01 is well tolerated when combined with intensive therapy for AML and appears associated with enhanced count recovery and treatment efficacy.

C-MYC-positive relapsed and refractory, diffuse large B-cell lymphoma: Impact of additional "hits" and outcomes with subsequent therapy.

BACKGROUND: The impact of MYC proto-oncogene, basic helix-loop-helix (MYC) translocations (with or without additional rearrangements involving the B-cell lymphoma 2 [BCL2] or BCL6 genes) on the response to salvage therapy and survival in patients with diffuse large B-cell lymphoma (DLBCL) who experience primary treatment failure is not well defined. METHODS: This was a multicenter, retrospective study of the impact of MYC, BCL2, and BCL6 rearrangements in patients with DLBCL who failed to achieve complete remission or relapsed within 6 months after they completed upfront chemoimmunotherapy. RESULTS: The authors examined response to salvage therapy, receipt of hematopoietic cell transplantation (HCT), and survival outcomes in MYC-negative (n = 120), MYC-positive single hit (SH) (n = 20), and MYC-positive double hit/triple hit (DH/TH) (n = 35) cohorts. The overall response rate in these cohorts to first salvage therapy (51%, 50%, and 54%, respectively) and receipt of HCT (52%, 40%, and 43%, respectively) were comparable between the 3 cohorts. The 2-year overall survival rate was 29.9% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 9.9% in the MYC-positive DH/TH cohort (P < .001), and no difference was observed between the SH and DH/TH cohorts (P = .8). The higher risk of death for patients with MYC-positive SH DLBCL (hazard ratio, 1.70; 95% confidence interval, 0.98-2.96; P = .06) and those with MYC-positive DH/TH DLBCL (hazard ratio, 2.22; 95% confidence interval, 1.41-3.50; P = .001) persisted after adjusting for covariates. For patients who underwent autologous HCT, the 2-year overall survival rate was 55.4% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 19.4% in the MYC-positive DH/TH cohort (P < .001). All 4 MYC-positive patients who underwent allogeneic HCT relapsed in <4 months. CONCLUSIONS: Patients with MYC-positive DLBCL who experience primary treatment failure have response rates to similar to those achieved by salvage therapy compared with their MYC-negative counterparts, but their survival is dismal irrespective of additional "hits" and HCT, representing an unmet medical need. Cancer 2017;123:4411-8. © 2017 American Cancer Society.

NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.